Chronic or intractable pain, such as may occur in conditions such as bone degenerative diseases and cancer, is a debilitating condition which is treated with a variety of analgesic agents, and often with opioid compounds, such as morphine. Although brain pathways governing the perception of pain are still incompletely understood, sensory afferent synaptic connections to the spinal cord, termed "nociceptive pathways," have been documented in some detail (McGeer, 1987). Analgesia, or the reduction of pain perception, can be effected by decreasing transmission along such nociceptive pathways.
Neuropathic pain is a particular type of pain that has a complex and variable etiology. It is generally a chronic condition attributable to complete or partial transection of a, nerve or trauma to a nerve plexus or soft tissue. This condition is characterized by hyperesthesia (enhanced sensitivity to a natural stimulus), hyperalgesia (abnormal sensitivity to pain), allodynia (widespread tenderness, characterized by hypersensitivity to tactile stimuli), and/or spontaneous burning pain. In humans, neuropathic pain tends to be chronic and may be debilitating.
Neuropathic pain is generally considered to be non-responsive or only partially responsive to conventional opioid analgesic regiments (Jadad, et al., 1992). Opioid compounds may also induce tolerance in patients, requiring increased dosages. At high doses, these compounds produce side effects, such as respiratory depression, which can be life threatening, and may also produce physical dependence in patients. For these reasons, alternate therapies for the management of chronic or neuropathic pain are widely sought.
Lidocaine is an well known analgesic compound with sodium channel blocking properties. It operates as a local anesthetic by inhibiting the ionic fluxes needed for conduction of impulses across neuronal membranes. several recent studies have also shown lidocaine to be useful in treatment of neuropathic and central pain. See, for example, Sotgui, et al., 1994, 1995 (neuropathic rat models); Rowbotham, et al., 1995 (postherpetic neuralgia); Fukuda, et al. 1994, Kastrup, et al., 1987, 1989; Ackerman, et al., 1991 (diabetic neuropathy); DeVulder, et al., 1993; Ellemann, et al., 1989 (cancer patients); Tanelian, et al., 1991 (acute nerve injury) and Edmondson, et al., 1993 (post stroke pain).
However, because of potentially serious side effects, which can include spinal block, respiratory arrest, and cardiac arrest, minimal dosages are recommended when lidocaine hydrochloride is administered systemically for anesthesia, and it must be administered under careful supervision (Physician's Desk Reference, 1994).
Lidocaine also has low water solubility (octanol/water partition coefficient=43 at pH 7.4). It is generally prepared as an acidic solution of the salt to promote solubility, although it is the nonionic (free base) form that permeates the nerve membrane and sheath (Tsai, et al., 1989).
It is therefore desirable to provide analgesic compounds which have low toxicity at effective dosage levels, have improved water solubility, and are effective in treatment of neuropathic pain.